The present invention relates to vitamin D derivatives having a hydroxy group at 24-position thereof, and particularly relates to vitamin D derivatives having a substituent at 2xcex2 position and a hydroxy group at 24-position.
Recently, some of the physiological activities of vitamins D have been revealed. It is known that a certain vitamin D, for example, 1xcex1, 25-dihydroxyvitamin D3, exhibits a variety of physiological activities such as a calcium metabolism-controlling activity, a proliferation-inhibiting activity and a differentiation-inducing activity on cells such as tumor cells, and an immune-controlling activity.
However, 1xcex1, 25-dihydroxyvitamin D3 disadvantageously causes hypercalcemia depending on the dose and/or the administration route and thus is not suitable for use as an antitumor agent, a therapeutic agent for rheumatic diseases, etc. In order to isolate such activities of the vitamin D derivatives, numerous vitamin D derivatives have been synthesized these days and their physiological activities were evaluated.
Among numerous vitamin D3 derivatives, some of those which have a substituent at the 2xcex2-position possess physiological activities such as calcium metabolism-controlling activity and differentiation-inducing activity on cells such as tumor cells and are known to be useful as a medicine, such as a therapeutic agent for diseases associated with abnormal calcium metabolism, such as osteoporosis, osteomalacia, etc. and an antitumor agent (Japanese Patent Publication (Kokoku) No. 3-14303, Japanese Patent Publication (Kokai) No. 61-267549 and Japanese Patent Publication (Kokai) No. 6-41059). Among them, 2xcex2-(3-hydroxypropoxy)-1xcex1, 25 -dihydroxyvitamin D3 is expected to be of practical use in treating osteoporosis, with a high blood level being able to be maintained for a long duration.
Vitamin D3 derivatives may be synthesized, for example, by epoxidation and then opening the A ring structure of a steroid compound (used as a starting material) so as to introduce the substituent to 2-position (Japanese Patent Publication (Kokai) No. 61-267549) or by coupling the A ring part and the CD ring part of the vitamin D derivative, which parts have been synthesized separately. Japanese Patent Publication (Kokai) No. 6-25039 and Japanese Patent Application No. 9-53316 (published as Japanese Patent Publication (Kokai) No. 10-251183) disclose processes for synthesizing the A ring part of vitamin D derivatives.
As described above, the 2xcex2-(3-hydroxypropoxy)-1xcex1, 25 -dihydroxyvitamin D3 has been developed as a useful medicine; at the same time, its metabolites are also under study. With recent progress in the study of 2xcex2-(3-hydroxypropoxy)-1xcex1, 25 -dihydroxyvitamin D3 metabolites, it has been suggested that some of the metabolites have their side chain hydroxylated. However, no report has been made concerning the synthesis of a 2xcex2-(3-hydroxypropoxy)-1xcex1, 25-dihydroxyvitamin D3 derivative of which the 24-position is hydroxylated.
One object of the present invention is to provide a novel vitamin D derivative of which 24-position is hydroxylated.
Another object of the present invention is to provide novel intermediates which are useful for synthesizing the above-mentioned novel vitamin D derivative of which 24 -position is hydroxylated, more specifically, intermediates corresponding to the A ring part and intermediates corresponding to the C ring part of the vitamin D derivative skeleton.
Still another object of the present invention is to provide a process by which the novel vitamin D derivative of the present invention of which 24-position is hydroxylated is synthesized by using the intermediates of the present invention.
Still another object of the present invention is to provide a process for synthesizing 2xcex2-(3-hydroxypropoxy)-1xcex1, 25-dihydroxyvitamin D3 by using the novel intermediates of the present invention.
With a view to attaining the above-mentioned objects, the inventors of the present invention investigated the various reactions involved in the synthesis of the CD ring part and A ring part of vitamin D skeleton and in the coupling of the CD ring part and the A ring part and, as a result, achieved the synthesis of the desired vitamin D3 derivative having a hydroxy group at 24-position by first synthesizing 1-[4,5-bis(t-butyldimethylsilyloxy)-1,5 -dimethylhexyl]-4-bromomethylene-7a-methyl-octahydro-1H-indene and 3,5-bis(t-butyldimethylsilyloxy)-4-(3 -t-butyldimethylsilyloxypropoxy)-1-octen-7-ine,separately as the CD ring part and the A ring part, respectively and coupling them together, thereby completing the present invention.
According to a first aspect of the present invention, there are provided vitamin D derivatives having the general formula (1): 
[wherein R1, R2, R3 and R4, which may be the same or different, represent a hydrogen atom or a protecting group; X and Y represent H or OR5, provided Y is OR5 when X is H and Y is H when X is OR5 (wherein R5 is a hydrogen atom or a protecting group and R1 and R5 may together form a vicinal-diol protecting group)].
Preferably, the 1-position of the general formula (1) is in R-configuration.
According to a second aspect of the present invention, there are provided compounds having the general formula (2): 
[wherein R1 and R6, which may be the same or different, represent a hydrogen atom or a protecting group; X and Y represent H or OR5, provided Y is OR5 when X is H and Y is H when X is OR5 (wherein R5 represents a hydrogen atom or a protecting group and R1 and R5 may together form a vicinal-diol protecting group)];
compounds having the general formula (3): 
[wherein R1 represents a hydrogen atom or a protecting group; X and Y represent H or OR5, provided Y is OR5 when X is H and Y is H when X is OR5 (wherein R5 represents a hydrogen atom or a protecting group and R1 and R5 may together form a vicinal-diol protecting group)]; and
compounds having the formula (4): 
[wherein R1 represents a hydrogen atom or a protecting group; X and Y represent H or OR 5, provided Y is OR5 when X is H and Y is H when X is OR5 (wherein R5 represents a hydrogen atom or a protecting group and R1 and R5 may together form a vicinal-diol protecting group)]. These compounds are useful as intermediates for the synthesis of compounds of the general formula (1).
According to a third aspect of the present invention, there are provided compounds having the general formula (5): 
(wherein R7 represents a trimethylsilyl group or a hydrogen atom; and R2, R3 and R4, which are the same or different, represent a hydrogen atom or a protecting group). These compounds are useful as intermediates for the synthesis of compounds of the general formula (1).
According to a fourth aspect of the present invention, there is provided a process for preparing vitamin D derivatives having the general formula (1): 
[wherein R1, R2, R3 and R4, which may be the same or different, represent a hydrogen atom or a protecting group; X and Y represent H or OR5, provided Y is OR5 when X is H and Y is H when X is OR5 (wherein R5 is a hydrogen atom or a protecting group and R1 and R5 may together form a vicinal-diol protecting group)] comprising:
reacting a compound having the general formula (4): 
[wherein R1 represents a hydrogen atom or a protecting group; X and Y represent H or OR5, provided Y is OR5 when X is H and Y is H when X is OR5 (wherein R5 represents a hydrogen atom or a protecting group and R1 and R5 may together form a vicinal-diol protecting group)]
with a compound of the general formula (5): 
(wherein R7 represents a hydrogen atom; and R2, R3 and R4, which are the same or different, represent a hydrogen atom or a protecting group).
In the above process, the OR2 group at the 3-position of the compound having the general formula (5) is in R-configuration and the 1-position of the compound having the general formula (1) is in R-configuration.
According to a fifth aspect of the present invention, there are provided a process for preparing vitamin D derivatives having the general formula (6): 
(wherein R1, R2, R3 and R4, which may be the same or different, represent a hydrogen atom or a protecting group) comprising:
reacting a compound having the general formula (7): 
(wherein R1 represents a hydrogen atom or a protecting group)
with a compound having the general formula (5): 
(wherein R7 represents a hydrogen atom; and R2, R3 and R4, which are the same or different, represent a hydrogen atom or a protecting group).
According to a sixth aspect of the present invention, there are provided pharmaceutical compositions comprising a vitamin D derivative having the general formula (1): 
[wherein R1, R2, R3 and R4, which may be the same or different, represent a hydrogen atom or a protecting group; X and Y represent H or OR5, provided Y is OR5 when X is H and Y is H when X is OR5 (wherein R5 is a hydrogen atom or a protecting group and R1 and R5 may together form a vicinal-diol protecting group)].
The pharmaceutical compositions of the present invention can be used, for example, as a therapeutic agent for diseases associated with abnormal calcium metabolism or an antitumor agent.